JPH09176155A - Sulfates of substituted triazoles, their pharmaceutical compositions and their use in therapy - Google Patents

Abstract

(57) Abstract: A sulfate salt of a substituted triazole derivative which is a selective agonist of a so-called "5-HT ₁ -like" receptor which acts on a 5-hydroxytryptamine (5-HT) receptor. Structural formula I: N, N-dimethyl-2- [5- (1,2,4-triazol-1-ylmethyl) -1H-indol-3-yl] ethylamine sulfate (2: 1) and its pharmaceutically acceptable Solvates. [Effect] A pharmaceutical composition particularly suitable for sublingual administration and intranasal administration can be obtained.

Description

Detailed Description of the Invention

[0001]

This invention relates to certain salts of pharmaceutically active agents. In particular, the present invention relates to the so-called “5-HT acting on 5-hydroxytryptamine (5-HT) receptor.
_It relates to the sulfates of substituted triazole derivatives that are selective agonists of ₁ -like "receptors. Therefore, the compounds are useful in the treatment of clinical conditions where selective agonists of these receptors are needed.

In recent years, 5-HT ₁ -which shows selective vasoconstrictor activity
-Like receptor agonists have been reported for use in the treatment of migraine [eg A. Doenicke et al., The Lancet , 19
88, Vol. 1, 1309-11]. Accordingly, salts of the present invention exhibiting selective 5-HT ₁ -like receptor agonist activity are useful for migraine and related conditions (e.g., cluster headache, chronic paroxysmal migraine headache, headache associated with vascular disorders, tension headache and It is especially useful for the treatment of childhood migraine.

European Patent Application No. 0497512 (August 5, 1992)
Discloses a class of substituted imidazole, triazole and tetrazole derivatives that are selective agonists of 5-HT ₁ -like receptors and are therefore particularly useful in the treatment of migraine and related conditions. There is.

The present invention relates to N, N-dimethyl-2- [5- (1,2,4-
Triazol-1-ylmethyl) -1H-indol-3-yl] ethylamine sulfate is provided. In particular, the present invention provides compounds of structural formula I:

[0005]

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N, N-dimethyl-2- [5- (1,2,4-triazol-1-ylmethyl) -1H-indol-3-yl] ethylamine sulfate (2: 1) and its hydrate, In particular, pharmaceutically acceptable solvates thereof, including 0.7 hydrate are provided.

The pharmaceutically acceptable salts of N, N-dimethyl-2- [5- (1,2,4-triazol-1-ylmethyl) -1H-indol-3-yl] ethylamine are generically , Within European Patent Application No. 0497512. Indeed, among others, the oxalate hemi-hydrate, its succinate and benzoate salts are disclosed in European Patent Application No. 0497512. However,
European Patent Application No. 0497512 does not describe the specific salts of structural formula I above or pharmaceutically acceptable solvates thereof.

It has been found that the salts of the above structural formula I have in some respects advantageous properties which are particularly useful for use as medicaments. For example, unlike many of the known drugs known for unpleasant tastes, the salts of Formula I have been found to be relatively tasteless.

In another aspect, the invention is directed to a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and a sulfate of formula I above or a pharmaceutically acceptable solvate thereof. Offer things.

The compounds of the present invention may be administered in oral, parenteral, intranasal, sublingual or rectal administration, or in unit dosage form for administration by inhalation or inhalation (eg tablets, pills,
Suitable for capsules, powders, particles, sterile solutions or suspensions, metered aerosol or liquid sprays, droplets, ampules, autoinjector devices or suppositories). Compositions of the present invention include, for example, Remington's Pharmaceutical
It can be conveniently compounded by a conventionally known method as described in Sciences , 17th edition., 1985.

For example, to produce a solid composition such as a tablet, the active ingredient may be converted into a pharmaceutically acceptable carrier such as microcrystalline cellulose, corn starch, lactose,
Sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gum)
And other pharmaceutical diluents: solid preformulation compositions comprising a homogeneous mixture of the salt of formula I above, for example, mixed with water.
mulation composition). Homogeneous in these pre-blended mixtures means that the active ingredient is homogeneously dispersed throughout the composition so that it can be readily subdivided into equally effective unit dosage forms (eg, tablets, pills, and capsules). I do. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.

Liquid forms in which the salts of the invention may be formulated for oral, parenteral or injectable administration include:
Aqueous solutions, optionally flavored syrups, aqueous or oily suspensions, and flavored emulsions, including edible oils (eg, cottonseed oil, sesame oil, coconut oil or peanut oil), elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums (eg, tragacanth, acacia), alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

For the treatment of migraine, the preferred dosage level is
About 0.01-250 mg / kg. Day, preferably about 0.05-100 mg / kg.
Days, especially about 0.05-5 mg / kg.day. The composition may be administered on a regimen of 1 to 4 times per day.

In one embodiment of the composition of the present invention, a salt of formula I as defined above or a pharmaceutically acceptable solvate thereof; one or more capable of bringing the oral vestibule to a pH of at least 7.5 after administration. A pharmaceutically acceptable buffer; and one or more pharmaceutically acceptable excipients, which are solid pharmaceutical compositions adapted for sublingual administration.

The sublingual region of the oral cavity is small, but has many blood vessels and lymph glands. Thus, the adsorption of specific molecules is fast, and a systemic therapeutic effect is obtained very quickly. A further advantage of the sublingual route is that drugs taken sublingually can enter the systemic circulatory system directly and prevent possible metabolism during passage through the liver. However, the majority of commercially available drugs are amines and are therefore basic. Natural pH 6.2 ~
In the physiological environment of the oral cavity of 7.4, such an ionized state of the basic drug is unfavorable for an acceptable absorption rate of the drug from the oral vestibule.

Literature [eg Rathbone and Hadgraft , In
It is known from tJPharmaceutics , (1991), 74 , 9-24] that the higher the pH of the oral formulation, the faster the absorption of the basic drug contained therein. For this reason, the sublingual formulations of the present invention include a buffer which, after administration, can bring the oral vestibule to a pH of at least 7.5.

Examples of typical solid compositions adapted for sublingual administration include tablets, in particular freeze-dried tablets [eg Zydis: US Pat. No. 4,371,516:
(Registered trademark) system]; capsules (including dry-filled capsules, liquid-filled soft gelatin capsules and hard gelatin capsules); powders; and particles. Preferably, the sublingual composition of the present invention is in tablet form.

The finished sublingual composition of the present invention may be of any convenient size and shape suitable for sublingual administration. If the composition is in tablet form, the tablet will usually be 50-50
It weighs 0 mg. Tablets preferably weigh around 220 mg.

The sublingual composition of the present invention comprises one or more pharmaceutically acceptable buffering agents which, after administration, can bring the oral vestibule to a pH of at least 7.5. As noted above, it is known that the absorption of basic drugs from the oral cavity can be enhanced when the pH in the oral vestibule is high. Accordingly, the solid sublingual formulation of the present invention comprises
If it is placed in the oral vestibule, it has the advantage that the pH of the mouth is increased and the absorption of the drug is enhanced compared to absorption from the corresponding unbuffered formulation.

The nature of the buffering agent used in the sublingual composition of the present invention is, provided that it is pharmaceutically acceptable and that the pH of the oral vestibule after administration can be at least 7.5. There is basically no limit. Those skilled in the art are aware of various buffers that can be suitably used in this context.
Examples of suitable buffering agents include glycine / sodium hydroxide, sodium carbonate, sodium bicarbonate and mixtures thereof. A preferred buffer system comprises a mixture of sodium carbonate and sodium bicarbonate.

The amount of buffer incorporated in the sublingual compositions of the present invention can vary over a wide range depending on the desired pH of the final composition. As already mentioned, it is important that the amount of buffer used keeps the oral vestibular pH level high after administration within physiological limits. For example, when using a buffer system consisting of a mixture of sodium carbonate and sodium bicarbonate,
At pH levels above about 9.6, it is found desirable to keep the pH of the compositions of the present invention below about 9.6, as the lower jaw will be considerably irritated and the mouth will feel burned. It was Therefore, if a mixture of sodium carbonate and sodium bicarbonate is used, the amount of sodium carbonate in the final composition should be between 5 and 20% by weight, calculated as anhydrous sodium carbonate or equivalent amount of hydrated sodium carbonate. Suitable is about 10% by weight; and the amount of sodium bicarbonate is preferably 15-35% by weight of the final composition, preferably 30% by weight.

The pharmaceutically acceptable excipients that are incorporated into the sublingual compositions of the present invention may be conveniently used in combination with the sublingual formulation. Representative excipients are described, for example, in Remington's Pharmaceutical Sciences (ibid.) And usually include a binder (eg, corn starch); a lubricant (eg, magnesium stearate); a compression aid (eg, cellulose, Lactose and mannitol); and disintegrating agents (eg, sodium starch glycolate and sodium carboxymethyl cellulose).

Since the sublingual composition of the present invention is to be administered by the oral route, the taste of the finished product of the composition is a factor to consider. Many buffers have an unpleasant taste. For example, a buffer system consisting of a mixture of sodium carbonate and sodium bicarbonate has been found to impart an unpleasant taste to formulations containing this system. For this reason, it is convenient to incorporate sweeteners and / or flavoring agents in the sublingual compositions of the present invention.

Suitable sweeteners include water-soluble natural sweeteners such as monosaccharides, disaccharides and polysaccharides (eg xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, invert sugar, maltose, Partially hydrolyzed starch); or solid corn syrup and sugar alcohols (eg, sorbitol, xylitol, mannitol, dihydrochalcone,
Glyciridin and steviarebaudiana (steviosid
e))]; Water-soluble artificial sweeteners [eg soluble saccharin salts, ie sodium or calcium salts of saccharin, cyclamate salts, free acid form of saccharin and synthetic sweeteners 3,4-dihydro-6-methyl-1. , 2,3-Oxathiazin-4-one 2,2-dioxide, especially its potassium (aces
ulfame-K), sodium and calcium salts]; dipeptide-based sweeteners [eg L-aspartyl-L-phenylalanine methyl ester]; and mixtures thereof. Saccharin sodium is a preferred sweetener.

In general, the amount of sweetener used will vary with the desired sweetness of the particular composition and, if necessary, the degree of unpleasant taste to be masked. For example, when the sweetener used is saccharin sodium, the amount incorporated is preferably 0-10% by weight of the final sublingual composition, and about 5% by weight.
Is preferred.

Examples of suitable flavoring agents for incorporation into the sublingual compositions of the present invention include synthetic flavor oils, fruit essences and natural flavor oils derived, for example, from plants, leaves and flowers; and mixtures thereof. Is mentioned. Specific examples include oils of spearmint oil, peppermint oil, cinnamon oil and Himekoji (methyl salicylate); citrus oil (derived from lemon, orange, grape, lime and grapefruit);
Fruit essences (eg, those derived from apples, strawberries, cherries and pineapples); and extracts (eg, kola extracts). A specific flavoring agent is peppermint NAEFCO / P05.51.

The amount of flavoring agent used with a sweetener is usually a matter of individual preference, but is influenced in particular by the degree of unpleasant taste to be concealed, if necessary. Generally, a suitable amount of flavoring agent is from 0 to 10% by weight of the final sublingual composition, with about 3% being preferred.

If desired, pharmaceutically acceptable coloring agents can also be suitably incorporated into the sublingual compositions of the present invention. A typical colorant is the internationally acceptable blue aluminum lake Blue
It is FD & C No.2. The coloring agent is 0 in the finished product of the composition.
Approximately 0.25% by weight, preferably in an amount of ~ 1.0% by weight.
Is preferred.

By properly adjusting the proportions of the individual components constituting the sublingual composition of the present invention, the long-term oral vestibular
It can be a final formulation that can exhibit the advantageous properties of maintaining a pH of at least 7.5, preferably at least 9.0.

The sublingual compositions of the present invention can be conveniently prepared by various standard methods known to those skilled in the art. Generally, known methods include direct compression and wet granulation.

[0031] Oral compositions are associated with nausea, eg, migraine, and can be disadvantageous for treating patients who are unable to tolerate oral compositions. Parenteral administration usually has the advantage of rapid absorption of the drug, but administration of this route may not be utilized by some patients, especially if a composition adapted for self-administration is available.

The salts of the formula I have in fact been found to have a surprisingly high solubility in water, making it possible in particular to prepare intranasal formulations in which the active ingredient is to be in a relatively concentrated aqueous solution. The water solubility of the salt of Formula I, expressed in terms of the free base, is
It was found to be about 170 mg / ml. This is, for example,
Under equivalent conditions, about 40 mg / ml N, N-dimethyl-2- [5-
(1,2,4-triazol-1-ylmethyl) -1H-indole
-3-yl] ethylamine benzoate (European patent application no.
It is comparable to the solubility of Example 18) of No. 0497512.

Furthermore, it has been found that the sulfates of the present invention exhibit an unexpectedly low tonicity. In theory, mO
The tonicity of a given solution, expressed as osmolality in smols, is calculated by the following equation:

[0034]

[Equation 1]

Where T is the theoretical tonicity (mOsml); C is the solution concentration (mg / ml); N is the number of ions per salt molecule; and M Is the molecular weight of the salt].

Applying the above equation to the salt of formula I above, the theoretical tonicity of the aqueous solution at a concentration of 189 mg / ml (equivalent to 160 mg / ml free base) can be calculated as follows.

[0037]

[Equation 2]

However, when measured by conventional practical methods (eg, osmometers using known freezing point depression methods), the concentration of the salt of formula I is 189 mg / ml (free base 16
The tonicity of the aqueous solution (equivalent to 0 mg / ml) was actually found to be only about 340 mOsml.

Various theoretical explanations have been made for the mechanism of action of the unexpected hypotonicity of the sulfate aqueous solution of the present invention. An example of the explanation is that as the salt dissolves, the free base ions aggregate into micelles, reducing the number of "particles" in the solution,
The value of the parameter N of theoretical tonicity in the above equation is much smaller. However, it will be understood that other descriptions are equally likely and none of these descriptions should be construed as limiting the scope of the invention.

The fact that the tonicity of the solutions of the salts according to the invention is low compared to the expected value is believed to reduce the local irritancy in the area of the body to which such solutions are administered. . This effect is particularly pronounced in areas with sensitive mucosa (eg, intranasal depressions). Thus, given the combination of high solubility described above and this property, the sulfates of formula I are ideal for the formulation of aqueous intranasal formulations.

The effect of tonicity on the stimulating properties of ionic solutions can be illustrated by various concentrations of aqueous sodium chloride solution. That is, the tonicity in the nasal cavity is 900 mOsmol [concentration 189 mg / ml
Administration of an aqueous solution of sodium chloride (compare theoretical tonicity of 891 mOsmol of salt of formula I above (equal to 160 mg / ml free base)] gives a considerable tingling sensation.
Such solutions have a very high osmotic pressure. On the other hand, tonicity 305mOsmol [concentration 189mg / ml (free base 160mg /
(equal to 1 ml) vs. the observed tonicity of 340 mOsmol observed for the salt of formula I above]] is completely satisfactory. At a tonicity of 305 mOsmol, the aqueous sodium chloride solution is isotonic. Therefore, the measured tonicity value of the sulfate of the invention at a concentration of 160 mg / ml (expressed as free base) was 340 mOsmol, which at this concentration was
This means that the aqueous solution has a slightly higher osmotic pressure.

For the reasons mentioned above, it can be seen that the salts according to the invention are particularly suitable for administration by the intranasal route.
Therefore, in a preferred embodiment of the composition of the present invention, 1
Comprising one or more pharmaceutically acceptable carriers and a sulfate salt of Formula I above or a pharmaceutically acceptable solvate thereof.
Provided is a pharmaceutical composition adapted for intranasal administration.

Intranasal formulations are usually supplied in liquid or dry powder form. A good intranasal formulation must be chemically and physically sufficiently stable and capable of consistently dispensing accurate dosages, even after prolonged storage at conditions that can vary in temperature from 0 to 40 ° C. Therefore, the active ingredient must be compatible with the excipients used in the formulation, for example, precipitating from a liquid formulation or solidifying a powder formulation to deliver an accurate prescribed amount. It should not aggregate into a state where it cannot. In order to maintain the intranasal formulation, especially the liquid formulation, preferably in the nasal passages of the patient after administration, a relatively small delivery volume, for example 50 to 200 μl, preferably about
It is desirable to deliver a unit dose of active ingredient in 100 μl. For this, a very soluble active ingredient is advantageous, since high concentrations of drug have to be used.
Clearly, the active ingredient must be formulated so as to be immediately absorbed by the nasal mucosa but without adverse effects (eg irritation).

As noted above, for intranasal administration, it has been found that the salts of the present invention can be conveniently administered in solution form.

The solution is usually aqueous. These may be prepared from water alone (eg sterile, pyrogen-free water) or water and pharmaceutically acceptable co-solvents (eg ethanol, propylene glycol and polyethylene glycol: eg PEG 400). .

Such solutions may also contain other additives such as preservatives (eg benzalkonium chloride and phenylethyl alcohol), buffers, tonicity-adjusting agents (eg sodium chloride), thickeners. , Absorption enhancers, flavoring agents (eg fragrances; menthol, eucalyptol, camphor and methyl salicylate, about 0.001 to about 0.5
% By weight) and sweeteners (eg saccharin or saccharin sodium, in an amount of about 0.01% to about 10% by weight, preferably 0.01-2% by weight).

The solutions of the present invention are preferably sterile and free of preservatives. Sterile formulations can be manufactured by conventional methods, for example, by aseptic manufacture or by sterilizing bulk products.

The solutions are applied directly to the nasal cavity by conventional means, for example, with a drip bottle, pipette or spray.
The formulations may be provided in single or multiple dose forms. In the case of multiple dose forms, it is desirable to have a means for metering the dose. In the case of a drip bottle or pipette, this may be accomplished by the patient administering a suitable, predetermined volume of solution.
In the case of spraying, it can be carried out, for example, by means of a metering atomizing spray pump.

Intranasal administration may be carried out using suitable propellants [eg chlorofluorocarbons (CFCs) such as dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane; hydrofluorocarbons (HFCs) such as 1,1,1,1. 2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane; hydrochlorofluorocarbon (HCFC), eg chlorodifluoromethane, 1,1,1-chlorodifluoroethane, 1,1- Dichloro-2,2,2-trifluoroethane, 1-chloro-1,2,2,2-
Tetrafluoroethane or 1,1,1-dichlorofluoroethane; carbon dioxide or other suitable gas] in a pressurized pack with an aerosol formulation. The dose of the drug can be controlled by a metering valve. Alternatively, a piezoelectric mechanism may be used to spray the required amount.

The pharmaceutical composition for intranasal administration containing the salt of the present invention is preferably in the form of an aqueous solution.

Accordingly, the present invention provides a substantially isotonic aqueous solution of a salt of formula I as defined above; as well as the use of such a solution in the manufacture of a pharmaceutical composition adapted for intranasal administration. I do.

Aqueous solutions of the salts of the present invention adapted for intranasal administration preferably have a pH of 4-8. The aqueous solution for intranasal administration of the salt of the present invention preferably has a pH of 5 to 7.
At a concentration (expressed as free base) of 160 mg / ml, the pH of the aqueous solution of the sulfate of formula I above was found to be about 5.8. Such a solution is particularly convenient since it is not necessary to adjust the pH before use. For solutions of strongly acidic salts with pH values outside the acceptable range, the pH must be adjusted by adding further additives, especially buffers, but this time was obtained because the tonicity would necessarily be high. The pharmaceutical properties of the solution are adversely affected. Nevertheless, if the pH of the aqueous solution of the salt of the formula I is to be adjusted, it can be conveniently carried out by conventional means, for example by adding the required amount of a pharmaceutically acceptable acid or base.

The aqueous solution of sulfate of the present invention has the advantage that it can be prepared by simply dissolving the salt in water. Alternatively, such a solution may contain 0.5-0.7 molar equivalents of concentrated sulfuric acid,
N, N-dimethyl-2, preferably together with 0.5 molar equivalent of sulfuric acid
Obtained by mixing 1 molar equivalent of [5- (1,2,4-triazol-1-ylmethyl) -1H-indol-3-yl] ethylamine in water.

For intranasal administration, the aqueous salt solutions of the present invention ideally contain the salt at a concentration of 1 mg / ml to 200 mg / ml, preferably 10 mg / ml to 190 mg / ml.

For intranasal administration, the salt of the present invention comprises
It may be conveniently formulated in unit dosage form. A convenient unit dosage formulation for intranasal administration is 0.1 mg to 0.1 mg of active ingredient.
100 mg, suitably 1-60 mg, preferably 2-40 mg,
It may be administered to either one or both nostrils. Ideally, one nostril will receive 1 mg to 35 mg of the active ingredient at a time.

Typical unit dosage formulations can be presented in unit dosage form, eg, sealed in vials of glass or plastic material, which can be filled and sealed in a conventional manner. Alternatively, sealed vials of plastic material may be manufactured by a form-fill-seal method. Ideally, the vials and the components of the pharmaceutical formulation to be filled therein are heat stable. The sealed vial may be autoclaved, e.g., at 121 ° C for at least 15 minutes, or the container may be gamma-irradiated and the solution then converted to a sterile, unit-dose vial that can be attached to a convenient delivery device prior to use. It can be sterilized by sterile filtration.
The unit dose volume is preferably 50-200 μl, for example 100 μl.

A preferred device for administering the intranasal formulation of the present invention is a Bespak multidose device (Bespak,
Kings Lynn, United Kingdom)
A single dose spray device as described in WO-A-93 / 00172,
Valois "Monospray" is one of them.

In another embodiment, the present invention provides a compound of the formula
II:

[0059]

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N, N-dimethyl-2- [5- (1,2,4-triazol-1-ylmethyl) -1H-indol-3-yl] ethylamine in about 0.5 molar equivalents in a suitable solvent. And a solvate thereof of the formula I as defined above, which comprises reacting with sulfuric acid of

The process is usually preferably carried out by stirring the reactants in the presence of a lower alkanol (eg ethanol or isopropyl alcohol) in an aqueous medium at room temperature.

The above-mentioned salt of the formula I or a solvate thereof can be prepared by reacting the compound of the formula I
Salts of compounds of the above formula II other than the sulfate (2: 1) of formula II may also be prepared by salt exchange comprising treating with a suitable sulfate.

Examples of suitable sulfates that can be used in the above salt exchange method include metal salts of sulfuric acid (eg, sodium sulfate or silver sulfate) and sulfated ion exchange resins.
The reaction is conveniently carried out in an aqueous medium.

The compounds of formula II above can be prepared by any one of a variety of methods that will be readily apparent to those skilled in the art. Since the compound of formula II contains an indole ring, a suitable method for making it is known from Fischer
Indole synthesis. This is the formula III:

[0065]

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The hydrazine derivative of the formula IV

[0067]

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It may be conveniently carried out by reacting with a compound of ## STR7 ## or a carbonyl-protected form thereof.

Suitable carbonyl-protected forms of compounds of formula IV include dimethyl and diethyl acetal derivatives.

This reaction is usually carried out at an elevated temperature of about 90 ° C. and 4%.
It is conveniently carried out by stirring the reactants in the presence of sulfuric acid.

The hydrazine derivative of formula III has the formula V:

[0072]

Embedded image

Can be prepared from the corresponding aniline by diazotization followed by reduction. The diazotization is conveniently carried out using sodium nitrite / concentrated hydrochloric acid and the diazo product obtained is treated, for example, with tin (II) chloride.
In situ reduction using / concentrated hydrochloric acid, sodium sulfite / concentrated hydrochloric acid or sodium sulfite / concentrated sulfuric acid.

The aniline derivative of the formula V has the formula VI

[0075]

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The corresponding nitro compound is usually prepared in the presence of a hydrogen donor (eg, ammonium formate)
Transfer hydrogenation with a hydrogenation catalyst (eg, palladium on carbon), or
It can be prepared by conventional catalytic hydrogenation or reduction using tin (II) chloride.

The nitro compound of formula VI can be prepared at room temperature in a sodium salt of 1,2,4-triazole, nitrobenzyl halide (eg, 4-nitrobenzyl bromide), preferably in N, N-dimethylformamide. It can be conveniently prepared by reacting. Alternatively, the compound of formula VI is prepared by reacting a nitrobenzyl halide (eg, 4-nitrobenzyl bromide) with 4-amino-1,2,4-triazole and then treating the resulting triazolium salt with nitric acid, It can be produced by subsequent deamination by neutralization. This latter transformation, which can be conveniently implemented as two separate steps or a "one pot" method combining both steps,
It is convenient to carry out using reaction conditions similar to those described in J. Org. Chem. , 1989, 54 , 731.

In still another embodiment, the present invention provides:
A method for treating and / or preventing a clinical condition requiring a selective agonist of a 5-HT ₁ -like receptor, wherein the salt of formula I or pharmaceutically acceptable to a patient in need of such treatment. A method is provided which comprises administering an effective amount of the possible solvates thereof. In certain embodiments of the invention, the salt of Formula I or a pharmaceutically acceptable solvate thereof is administered in the form of a solution, preferably an aqueous solution adapted to be administered intranasally.

The present invention provides a drug, preferably a solution, preferably a solution, adapted to be administered intranasally to treat and / or prevent a clinical condition requiring a selective agonist of 5-HT ₁ -like receptor. Further provides the use of a salt of formula I as defined above, or a pharmaceutically acceptable solvate thereof, to prepare an aqueous solution.

[0080]

The following non-limiting examples are intended to illustrate the invention.

Production Example 1 Step (i): 1- (4-nitrobenzyl) -4-amino-4H-1,
2,4- Triazolium bromide 4-amino-1,2,4-triazole (250g, 2.976mol) and 4-nitrobenzyl bromide (Janssen, 99%, 617.5g, 2.
A mixture of 83 mol) of isopropyl alcohol (5.66 l) was refluxed with stirring. The mixture went into solution and almost immediately afterwards the required triazolium salt crystallized under reflux. The mixture was stirred and heated at reflux for 7.5 hours then allowed to cool to room temperature overnight. The next day, mix the mixture at 0-5 ° C.
After cooling to room temperature and holding for 1 hour, the product is filtered, washed with a little isopropyl alcohol and dried under vacuum at 50 ° C. to give the title triazolium salt (808 g, 95%) as a white solid.
was gotten. Melting point 199 ° C (decomposition).

Step (ii): 1- (4-nitrobenzyl) -1,
A solution of 2,4-triazole sodium nitrite (206 g, 2.98 mol) in water (840 ml) is a suspension of the above triazolium salt (808 g, 2.69 mol) in water (5.6 l) and concentrated hydrochloric acid (505 ml). 0-5 ° C
Was added to the surface over 70 minutes. 15 pale yellow slurry
The mixture was stirred for minutes at <5 ° C and then warmed to 25 ° C over 1 hour. The colorless solution was adjusted to pH 9 by adding aqueous ammonia solution (380 ml, 18N) keeping the temperature <30 ° C. The mixture was cooled to 0-5 ° C. and stirred for 1 hour. The solids were collected by filtration and the aqueous ammonium hydroxide solution (20 ml, 18
It was washed with water (400 ml) containing N 2) and then dried at 50 ° C. under reduced pressure to give the title nitro compound (535 g, 97%). Melting point 102-103 ° C.

Step (iii) 1- (4-aminobenzyl)-
1,2,4-triazole Methanol (8l) in the above nitro compound (803g, 3.9m
ol), ammonium formate (1.16kg, 18.4mol)
And 10% Pd / C (28g) at 30 ℃ under nitrogen atmosphere.
Warmed to. Stop heating and cool to a temperature of 35-45 ° C 2
The heat of reaction was controlled by holding for a period of time. The reaction mixture was cooled to 20 ° C. and the catalyst was filtered off using Hyflo filter aid. The filter pad was washed with methanol (21). The filtrate was concentrated and the residue was diluted with ethyl acetate (12 l) and water (1.57 l). The lower aqueous layer was treated to pH 9 with aqueous ammonium hydroxide solution (10 ml, 18N). The aqueous layer was separated and extracted with ethyl acetate (2x6l and 3l). The combined extracts were combined with saturated aqueous sodium hydrogen carbonate solution (1.57
Washed with l), dried and evaporated under reduced pressure to give the title amine (679g, 99%). Melting point 127-128 [deg.] C.

Step (iv): N, N-dimethyl-2- [5- (1,2,
4-triazol-1-ylmethyl) -1H-indole-3-y
Lu] ethylamine sodium nitrite (16.7g, 0.24mol) in water (22.7ml)
A solution of the above amine (40 g, 0.23 mol) in hydrochloric acid (65.3
ml) and water (162 ml) on the surface of the solution,
It was kept at 5 ° C. The solution was stirred at 0-5 ° C for 1 hour. The solution was added to a suspension of sodium sulfite (72.4g, 0.57mol) in water (227ml) cooled to 5-10 ° C under a nitrogen atmosphere. Stir the red solution at 5-10 ° C for 10 minutes and over 20 minutes
The temperature was raised to 20 ° C, and the mixture was heated to 70 ° C over 45 minutes. The solution
The mixture was stirred at 70 ° C for 2.5 hours and cooled to 65 ° C. Concentrated sulfuric acid (56.8
ml) was added to this solution over 15 minutes keeping the temperature at 70-80 ° C. The solution was stirred under a nitrogen atmosphere at 70 ° C for 2 hours and then allowed to cool to 20 ° C overnight. The resulting hydrazine solution was warmed to 25 ° C and treated with 4- (N, N-dimethylamino) -1,1
-Dimethoxybutane (44.3g, 0.28mol) at temperature <23
The mixture was added over 15 minutes while maintaining the temperature at 0 ° C. 30 ~ 35 ℃ solution
For 30 minutes. Heat the mixture to 90 ° C. over 30 minutes,
Hold at 90-93 ° C for 15 minutes. Cool the mixture to 15 ° C and use Hyfl
o Filter aid (68g) was added followed by aqueous ammonium hydroxide (200ml, 18N) to adjust the pH to 11-12. The mixture was filtered and the filtrate and Hyflo were extracted with ethyl acetate (5 x 300 ml). Dehydrate the extract (Na ₂ S
O ₄ ) and evaporated under reduced pressure. The residue is converted to silica gel (550
g) chromatography (ethyl acetate: methanol = 8)
0:20 → 50:50). Fractions containing product were evaporated under reduced pressure to give the title compound (27.8 g, 45%) in the free base form.
%)was gotten.

Example 1 N, N-dimethyl-2- [5- (1,2,4-triazol-1-ylme
Chill) -1H-indol-3-yl] ethylamine ・ 0.5 sulfur
Acid salt / 0.7 hydrate Sulfuric acid (1N, 1.17 ml) was added to N, N-dimethyl-2- [5- (1,2,4-
Triazol-1-ylmethyl) -1H-indol-3-yl] ethylamine (0.63g, 2.34mmol) in water (0.73ml)
And to a stirred solution in isopropyl alcohol (15.9 ml). Nuclei were added to the mixture and cooled to 0 ° C. The reaction mixture was filtered and the solid product was washed with diethyl ether (100 m
washed with l), then under vacuum and dried at 60 ° C., notation
0.5 sulphate (0.68 g, mp 233-234 ° C) was obtained.

C ₁₅ H ₁₉ N ₅ .0.5 H ₂ SO ₄ .0.7 H ₂ O
Calculated for: C, 54.43; H, 6.52; N, 21.16; S, 4.
84%. Found: C, 54.45; H, 6.35; N, 21.23; S, 4.66.
%. Example 2 Buffered sublingual tablet N, N-dimethyl-2- [5- (1,2,4-triazol-1-ylmethyl) -1H-indole- containing 50 μg of active ingredient (expressed as free base ) 3-yl] ethylamine ・ 0.5 sulfate ・ 0.7 hydrate 0.056mg Avicel PH 200 91.194mg Starch 1500 22.0 mg Sodium bicarbonate 67.5 mg Anhydrous sodium carbonate 20.0 mg Blue FD & C No.2 Aluminum lake 0.55 mg Saccharin sodium 11.0 mg Peppermint NAEFCO / P05.51 6.6 mg Magnesium stearate 1.1 mg Total weight 220.0 mg All ingredients except magnesium stearate were mixed together in a suitable blender. The resulting mixture was lubricated with magnesium stearate and compressed on a tablet press.

Example 3 Buffered sublingual tablet N, N-dimethyl-2- [5- (1,2,4-triazol-1-ylmethyl) -1H containing 20 mg of active ingredient (expressed as free base ) -Indole-3-yl] ethylamine 0.5 sulphate 0.7 hydrate 22.34 mg Avicel PH 200 68.91 mg starch 1500 22.0 mg sodium bicarbonate 67.5 mg anhydrous sodium carbonate 20.0 mg Blue FD & C No.2 aluminum lake 0.55 mg sodium saccharin 11.0 mg Peppermint NAEFCO / P05.51 6.6 mg Magnesium stearate 1.1 mg Total weight 220.0 mg All ingredients except magnesium stearate were mixed in a suitable blender. The resulting mixture was lubricated with magnesium stearate and compressed on a tablet press.

Examples 4 and 5 Sterile intranasal formulation Example 4 Example 5 Compound of formula (II) 0.85 mg 170 mg Sulfuric acid (concentrated) BP 0.155 mg 30.9 mg Bulk water for injection Ph.Eur. 1 ml The compound of formula (II) was dissolved in sulfuric acid pre-diluted with water. The solution was adjusted to a predetermined amount.

For example, by filling the vial with the present solution, sealing the vial, and autoclaving at 121 ° C. for 15 minutes or more to sterilize the vial, or sterilizing by filtration and aseptically transferring to a sterilized container, It may be intranasally packaged for administration.

Examples 6 and 7 Preservative Intranasal Formulation Example 6 Example 7 Compound of Formula (II) 0.85 mg 170 mg Sulfuric acid (concentrated) BP 0.155 mg 30.9 mg Phenylethyl alcohol USP 4.0 mg 4.0 mg Benzalco Numium chloride USNF 0.2 mg 0.2 mg Purified water BP Up to 1 ml The compound of formula (II) was dissolved in sulfuric acid which had been previously diluted with water. Phenylethyl alcohol and benzalkonium chloride were added to adjust the solution to a predetermined amount.

Similarly, the compound 1 of the formula (II)
Preservative formulations containing 5, 10, 50, 80, 100 and 150 mg / ml were prepared.

In one or both nostrils of a patient suffering from mild or severe migraine, a compound of formula (II) 0.1,
To deliver doses of 1, 5, 10 or 17 mg, a unit dose volume of 100 μl may be administered.

Examples 8 and 9 Sterile Intranasal Formulation Example 8 Example 9 Compound of Formula (I) 1 mg 200 mg Bulk Water for Injection Ph.Eur. Up to 1 ml Compound of Formula (I) Was dissolved in water and adjusted to a predetermined amount.

For intranasal administration, the solution is, for example, filled into a vial, sealed and then sterilized by autoclaving the vial at 121 ° C. for 15 minutes or more, or sterilized by filtration and aseptically. It may be packaged by transferring to a sterile container.

Examples 10 and 11 Another preservative intranasal formulation Example 10 Example 11 Compound of formula (I) 1 mg 200 mg Benzalkonium chloride 0.2 mg 0.2 mg Purified water BP to 1 ml Amount The compound of formula (I) was dissolved in water. Benzalkonium chloride was added to adjust the solution to a predetermined volume.

Examples 12-15 Sterile intranasal formulations Example 12 Example 13 Compound of formula (II) 5 mg 50 mg Sulfuric acid (concentrated) BP 0.91 mg 9.1 mg Bulk water for injection Ph.Eur. 1 ml Example 14 Example 15 Compound of formula (II) 100 mg 160 mg Sulfuric acid (concentrated) BP 18.2 mg 29.1 mg Bulk water for injection Ph.Eur. Up to 1 ml of compound of formula (II) Was dissolved in sulfuric acid which had been diluted before. The solution was adjusted to a predetermined amount.

This formulation was filled into vials in 100 μl aliquots, the vials were sealed and the contents were stored at 121 ° C. for 15 minutes.
It was sterilized by autoclaving for more than a minute. Alternatively, the solution may be filtered and sterilized by aseptically filling a sterile vial.

Compound of formula (II) 0.5 in one or both nostrils of a patient suffering from mild or severe migraine,
To deliver doses of 5, 10 or 16 mg, a unit dose volume of 100 μl may be administered.

Examples 16 and 17 Sterile intranasal formulation Example 16 Example 17 Compound of formula (II) 160 mg 160 mg Sulfuric acid (concentrated) BP 29.1 mg 29.1 mg Saccharin sodium BP 10 mg 20 mg Bulk water for injection Ph.D. Eur. Amount to 1 ml The compound of formula (II) was dissolved in sulfuric acid pre-diluted with water.
This solution was adjusted to about 90% by volume, saccharin was dissolved therein, and finally adjusted to a predetermined amount.

The formulation was filled into vials in 100 μl aliquots, the vials were sealed, and the vials were sealed at 121 ° C. for 15
It was sterilized by autoclaving for more than a minute. Alternatively, the solution may be filtered and sterilized by aseptically filling a sterile vial.

To deliver a dose of 16 mg of a compound of formula (II) to one or both nostrils of a patient suffering from mild or severe migraine, a unit dose volume of 100 μl may be administered.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication location // (C07D 403/06 209: 14 249: 08) (72) Inventor Victor G. Matatsusa United Kingdom Nation, S.G. 9.0 L.A., Hartfordshire, Fannyuk Peram, The Datsk Street Burns (no street number) (72) Inventor Kyaroll Olive United States, Pennsylvania 19446, Landsdale , Braeburn Terrace 1007 (72) Inventor Kendal G. Pitt England, A.L. 9.5 Day E, Heartfordshire, Hattfield, Bull Stagg Green 110 (72) Invention Person David E Story Ame Rica United States, Pennsylvania 19446, Landsdale, Braeburn Terrace 1007 (72) Inventor Leslie Jay Street UK, C.M.7S.S.T., Essets, Harlow, Spruce Hill 99 (72) Inventor Alexander Lichyard Guyblin England, C.M. 18/6 J.E.X, Essets, Harlow, Spencers Croft. 13

Claims (12)

[Claims] 1. A N, N-dimethyl-2- [5- (1,2,4-triazol-1-ylmethyl) -1H-indol-3-yl containing one or more pharmaceutically acceptable carriers. ] Ethylamine Sulfate or Structural Formula I: N, N-dimethyl-2- [5- (1,2,4-triazol-1-ylmethyl) -1H-indol-3-yl] ethylamine sulfate (2: 1) or pharmaceutically acceptable thereof A selective agonist pharmaceutical composition that acts on the 5-hydroxytryptamine receptor, including a solvate. 2. A sulfate of N, N-dimethyl-2- [5- (1,2,4-triazol-1-ylmethyl) -1H-indol-3-yl] ethylamine or a structural formula I: ] N, N-dimethyl-2- [5- (1,2,4-triazol-1-ylmethyl) -1H-indol-3-yl] ethylamine sulfate (2: 1) or pharmaceutically acceptable thereof Sublingual administration comprising a solvate; one or more pharmaceutically acceptable buffers capable of bringing the oral vestibule after administration to at least pH 7.5; and one or more pharmaceutically acceptable excipients A selective agonist pharmaceutical composition acting on a solid 5-hydroxytryptamine receptor thus obtained. 3. One or more pharmaceutically acceptable carrier is N, N-dimethyl-2- [5- (1,2,4-triazol-1-ylmethyl) -1H-indol-3-yl. ] Ethylamine Sulfate or Structural Formula I: N, N-dimethyl-2- [5- (1,2,4-triazol-1-ylmethyl) -1H-indol-3-yl] ethylamine sulfate (2: 1) or one or more pharmaceutically A selective agonist pharmaceutical composition acting on the 5-hydroxytryptamine receptor adapted for intranasal administration, including an acceptable solvate thereof. 4. The composition according to claim 3, which is formulated in the form of an aqueous solution. 5. Composition according to claim 4, characterized in that it is in the form of a solution in sterile, pyrogen-free water. 6. The composition according to claim 4, wherein the salt is contained at a concentration of 1 mg / ml to 200 mg / ml. 7. The composition according to claim 6, wherein the salt is contained at a concentration of 10 mg / ml to 190 mg / ml. 8. The composition of claim 7, wherein the salt is included at a concentration of about 189 mg / ml. 9. A composition according to any one of claims 3 to 8 which is formulated in a unit dosage form and contains the active ingredient in an amount of from 0.1 mg to 100 mg. 10. The composition according to claim 9, wherein the unit dose volume is 50 to 200 μl. 11. A pharmaceutically acceptable carrier and N, N-
Dimethyl-2- [5- (1,2,4-triazol-1-ylmethyl) -1H-indol-3-yl] ethylamine sulfate or structural formula I: N, N-dimethyl-2- [5- (1,2,4-triazol-1-ylmethyl) -1H-indol-3-yl] ethylamine sulfate (2: 1) or its pharmaceutically acceptable 11. Mixing with a solvate thereof, according to any one of claims 1 to 10.
A method for producing the pharmaceutical composition according to the item 1. 12. (A) N, N-dimethyl-2- [5- (1,2,4-
Triazol-1-ylmethyl) -1H-indol-3-yl] ethylamine sulfate or structural formula I: N, N-dimethyl-2- [5- (1,2,4-triazol-1-ylmethyl) -1H-indol-3-yl] ethylamine sulfate (2: 1) or pharmaceutically acceptable The solvate is dissolved in water; or (B) Structural Formula II: N, N-dimethyl-2- [5- (1,2,4-triazol-1-ylmethyl) -1H-indol-3-yl] ethylamine in 1 molar equivalent and concentrated sulfuric acid 0.5-0.7 molar equivalent The method for producing the pharmaceutical composition according to any one of claims 4 to 10, which comprises mixing in water.